A large subset of genes associated with autism are transcription factors or epigenetic regulators whose disruption causes broad dysregulation of gene expression during all stages of brain development. This dysregulation perturbs the hierarchy of progenitors that generates the adult brain, altering its cellular composition and organization and thereby contributing to the autism phenotype. However, current approaches are limited in longitudinally tracking these alterations in gene expression throughout neurogenesis. Therefore, it remains challenging to connect mutations in autism-associated genes with alterations of neuronal composition, organization and function in the brain.

To help address this gap, Reza Kalhor plans to build upon his earlier SFARI Bridge to Independence Award on high-throughput cell fate analysis¹ to establish mouse models for longitudinal recording of gene expression histories in cells’ genomes. These mice will be used to record the expression of autism-associated genes such as Chd7, Pax6 and Mef2c over all stages of brain development in mouse models of autism, including Chd8 and Mecp2 knockout mice, during brain development. These recordings will in turn allow Kalhor to map how gene expression networks are altered in brain progenitors and how these changes affect the hierarchy of brain progenitors. This research will help connect mutations associated with autism to changes in brain organization and function through mapping their effects on the behavior of brain progenitors.

1. Fang W. et al. Cell 185, 4604-4620 (2022) PubMed